tbuckley/cabot-search huggingface dataset:
DGMP: Identifying Cancer Driver Genes by Jointing DGCN and MLP from Multi-Omics Genomic Data
Authors: Shao-Wu Zhang, Jing-Yu Xu, Tong Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Identification of cancer driver genes plays an important role in precision oncology research, which is helpful to understand cancer initiation and progression. However, most existing computational methods mainly used the protein–protein interaction (PPI) networks, or treated the directed gene regulatory networks (GRNs) as the undirected gene–gene association networks to identify the cancer driver genes, which will lose the unique structure regulatory information in the directed GRNs, and then affect the outcome of the cancer driver gene identification. Here, based on the multi-omics pan-cancer data (i.e., gene expression, mutation, copy number variation, and DNA methylation), we propose a novel method (called DGMP) to identify cancer driver genes by jointing directed graph convolutional network (DGCN) and multilayer perceptron (MLP). DGMP learns the multi-omics features of genes as well as the topological structure features in GRN with the DGCN model and uses MLP to weigh more on gene features for mitigating the bias toward the graph topological features in the DGCN learning process. The results on three GRNs show that DGMP outperforms other existing state-of-the-art methods. The ablation experimental results on the DawnNet network indicate that introducing MLP into DGCN can offset the performance degradation of DGCN, and jointing MLP and DGCN can effectively improve the performance of identifying cancer driver genes. DGMP can identify not only the highly mutated cancer driver genes but also the driver genes harboring other kinds of alterations (e.g., differential expression and aberrant DNA methylation) or genes involved in GRNs with other cancer genes. The source code of DGMP can be freely downloaded from https://github.com/NWPU-903PR/DGMP.
TNF Receptors Choose HSC Fate in Supporting<i>Dnmt3a</i>-Mutant Clonal Hematopoiesis
Authors: Katia E. Niño, Eric M. Pietras
Journal: Cancer Discovery (2022)

Summary: TNFα receptor signaling distinctly promotes self-renewal and lymphoid differentiation in Dnmt3a-mutant hematopoietic stem cells, contributing to clonal hematopoiesis of indeterminate potential. See related article by SanMiguel et al., p. 2763 (3).
Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2
Authors: Dapeng Li, Anjiang Sun, Liang Zhang, Zhao Ding, Fangzheng Yi, Xue Yang, Zixi Wang, Xu Chen, Weiwei Liu, Shixian Liu, Hailong Shen, Manli Miao, Ling Zhang, Ping Liu, Yuchen Liu, Shihong Su, Hailiang Huang, Can Huang, Zhongdong Hu, Hongbing Zhang, Xiaojun Zha, Yehai Liu
Journal: Theranostics (2022)

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck, and it has shown increasing incidence and mortality.The mechanistic target of rapamycin complex 1 (mTORC1) is frequently dysregulated in LSCC, but its underlying mechanisms remain unclear.Methods: Establishment of a novel LSCC cell line using primary LSCC tumor tissues with dysregulated mTORC1 activity and then stable knockdown of Raptor (an mTORC1 specific component) in this cell line.Transcriptomic sequencing, quantitative real-time PCR, western blot analysis, and immunofluorescence assays were used to identify the crucial downstream effector of mTORC1.A series of experiments were conducted to investigate the functions and underlying mechanisms of the mTORC1 target gene in LSCC progression.Clinical LSCC samples were used to evaluate the association of mTORC1 and its downstream targets with clinicopathological features and patient prognosis.Finally, the influence on cisplatin (CDDP) sensitivity upon depletion of the mTORC1 target gene was assessed using a cell culture system, a cell line-derived xenograft (CDX) model, and a patient-derived xenograft (PDX) model. Results:We successfully established a novel LSCC cell line with hyperactivated mTORC1 activity and then identified integrin subunit alpha 5 (ITGA5) as a novel functional downstream effector of mTORC1 in the progression of LSCC.Elevated ITGA5 promotes LSCC progression through augmentation of ephrin-B2 (EFNB2).Clinical data analysis indicated that the activation of the mTORC1-ITGA5-EFNB2 signaling pathway is associated with malignant progression and poor prognosis of LSCC patients.Inhibition of ITGA5 significantly sensitized LSCC cells to CDDP.Conclusions: Our findings highlight a novel molecular mechanism for the tumorigenesis driven by deregulated mTORC1 signaling in LSCC, suggesting that the ITGA5-EFNB2 axis may be a therapeutic target for the treatment of mTORC1-related LSCC.
A Deep Dive into the Circulating ctDNA Cosmos to Vanquish Neuroblastoma
Authors: Hedwig E. Deubzer, Kathy Astrahantseff, Marco Lodrini
Journal: Cancer Discovery (2022)

Summary: Single biopsies fail to reflect intratumor heterogeneity and tumor evolution. In this issue of Cancer Discovery, Bosse and colleagues show an important role for circulating cell-free tumor DNA sequencing to detect the genomic evolution of neuroblastoma under ALK inhibitor therapy and identify novel (sub)clonal pathogenic variants involved in disease progression under conventional therapy. See related article by Bosse et al., p. 2800 (5).
Gut epithelial barrier damage caused by dishwasher detergents and rinse aids
Authors: Ismail Ogulur, Yagiz Pat, Tamer Aydin, Duygu Yazici, Beate Rückert, Yaqi Peng, Juno Kim, Urszula Radzikowska, Patrick Westermann, Milena Sokolowska, Raja Dhir, Mubeccel Akdis, Kari Nadeau, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2022)
Myopericarditis After COVID-19 mRNA Vaccination Among Adolescents and Young Adults
Authors: Jun Yasuhara, Kaihei Masuda, Tadao Aikawa, Takuro Shirasu, Hisato Takagi, Simon Lee, Toshiki Kuno
Journal: JAMA Pediatrics (2022)

Published data on COVID-19 mRNA vaccine-associated myopericarditis in adolescents and young adults have been derived from small case series, national population-based studies, or passive reporting systems. Pooled evidence from a larger, international cohort is scarce.To investigate the clinical features and early outcomes associated with myopericarditis after COVID-19 mRNA vaccination in a heterogeneous population of adolescents and young adults.PubMed and EMBASE were searched through August 2022. Language restrictions were not applied.Observational studies and case series describing COVID-19 vaccine-associated myopericarditis in adolescents and young adults aged 12 to 20 years and reporting clinical characteristics and early outcomes were included.Two independent investigators extracted relevant data from each study. One-group meta-analysis in a random effects model was performed. The Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology reporting guidelines were followed.The primary outcomes were clinical features and early outcomes for COVID-19 mRNA vaccine-associated myopericarditis, including incident rate, cardiac findings, hospitalization, intensive care unit (ICU) admission, and in-hospital mortality.A total of 23 observational studies were identified, including 854 individuals (mean age, 15.9 [95% CI, 15.5-16.2] years) with COVID-19 vaccine-associated myopericarditis. Male sex was predominant, at 90.3% (95% CI, 87.3%-93.2%) of individuals. The incident rate was higher after the second dose than the first dose, with 74.4% (95% CI, 58.2%-90.5%) of events occurring after the second dose. Most patients (84.4% [95% CI, 80.5%-88.3%] of patients) had preserved left ventricular (LV) function. Of the 15.6% (95% CI, 11.7%-19.5%) of patients with LV systolic dysfunction (LV ejection fraction [LVEF] <55%), most (14.1% [95% CI, 10.2%-18.1%]) were mild (ie, LVEF 45%-54%), and only 1.3% (95% CI, 0%-2.6%) of patients had severe LV systolic dysfunction (ie, LVEF<35%). Interestingly, cardiac magnetic resonance imaging revealed late gadolinium enhancement in 87.2% (95% CI, 79.8%-94.7%) of patients. Although 92.6% (95% CI, 87.8%-97.3%) of patients were hospitalized and 23.2% (95% CI, 11.7%-34.7%) of patients required ICU admission, inotropes were used in only 1.3% (95% CI, 0%-2.7%) of patients, no patients died or required mechanical support, and the hospital length of stay was 2.8 (95% CI, 2.1-3.5) days.This systematic review and meta-analysis found low incidence rate and largely favorable early outcomes of COVID-19 mRNA vaccine-associated myopericarditis in adolescents and young adults from a wide range of populations. These findings are reassuring but continued follow-up is warranted.
Nanotechnology‐based electrochemical biosensors for monitoring breast cancer biomarkers
Authors: Hassan Nasrollahpour, Balal Khalilzadeh, Mohammad Hasanzadeh, Reza Rahbarghazi, Pedro Estrela, Abdolhossein Naseri, Savas Tasoglu, Mika Sillanpää
Journal: Medicinal Research Reviews (2022)

Abstract Breast cancer is categorized as the most widespread cancer type among women globally. On‐time diagnosis can decrease the mortality rate by making the right decision in the therapy procedure. These features lead to a reduction in medication time and socioeconomic burden. The current review article provides a comprehensive assessment for breast cancer diagnosis using nanomaterials and related technologies. Growing use of the nano/biotechnology domain in terms of electrochemical nanobiosensor designing was discussed in detail. In this regard, recent advances in nanomaterial applied for amplified biosensing methodologies were assessed for breast cancer diagnosis by focusing on the advantages and disadvantages of these approaches. We also monitored designing methods, advantages, and the necessity of suitable (nano) materials from a statistical standpoint. The main objective of this review is to classify the applicable biosensors based on breast cancer biomarkers. With numerous nano‐sized platforms published for breast cancer diagnosis, this review tried to collect the most suitable methodologies for detecting biomarkers and certain breast cancer cell types.
Estimation of Neutral Mutation Rates and Quantification of Somatic Variant Selection Using cancereffectsizeR
Authors: Jeffrey D. Mandell, Vincent L. Cannataro, Jeffrey P. Townsend
Journal: Cancer Research (2022)

Abstract Somatic nucleotide mutations can contribute to cancer cell survival, proliferation, and pathogenesis. Although research has focused on identifying which mutations are “drivers” versus “passengers," quantifying the proliferative effects of specific variants within clinically relevant contexts could reveal novel aspects of cancer biology. To enable researchers to estimate these cancer effects, we developed cancereffectsizeR, an R package that organizes somatic variant data, facilitates mutational signature analysis, calculates site-specific mutation rates, and tests models of selection. Built-in models support effect estimation from single nucleotides to genes. Users can also estimate epistatic effects between paired sets of variants, or design and test custom models. The utility of cancer effect was validated by showing in a pan-cancer dataset that somatic variants classified as likely pathogenic or pathogenic in ClinVar exhibit substantially higher effects than most other variants. Indeed, cancer effect was a better predictor of pathogenic status than variant prevalence or functional impact scores. In addition, the application of this approach toward pairwise epistasis in lung adenocarcinoma showed that driver mutations in BRAF, EGFR, or KRAS typically reduce selection for alterations in the other two genes. Companion reference data packages support analyses using the hg19 or hg38 human genome builds, and a reference data builder enables use with any species or custom genome build with available genomic and transcriptomic data. A reference manual, tutorial, and public source code repository are available at https://townsend-lab-yale.github.io/cancereffectsizeR. Comprehensive estimation of cancer effects of somatic mutations can provide insights into oncogenic trajectories, with implications for cancer prognosis and treatment. Significance: An R package provides streamlined, customizable estimation of underlying nucleotide mutation rates and of the oncogenic and epistatic effects of mutations in cancer cohorts.
Association of Pneumococcal Conjugate Vaccine Use With Hospitalized Pneumonia in Medicare Beneficiaries 65 Years or Older With and Without Medical Conditions, 2014 to 2017
Authors: Miwako Kobayashi, Michael W. Spiller, Xiyuan Wu, Rongrong Wang, Yoganand Chillarige, Michael Wernecke, Thomas E. MaCurdy, Jeffery A. Kelman, Li Deng, Nong Shang, Cynthia G. Whitney, Tamara Pilishvili, Fernanda C. Lessa
Journal: JAMA Internal Medicine (2022)

The association of 13-valent pneumococcal conjugate vaccine (PCV13) use with pneumonia hospitalization in older adults, especially those with underlying medical conditions, is not well described.To evaluate the association of PCV13 use with pneumonia, non-health care-associated (non-HA) pneumonia, and lobar pneumonia (LP) hospitalization among US Medicare beneficiaries 65 years or older.This cohort study with time-varying exposure assignment analyzed claims data from US Medicare beneficiaries 65 years or older enrolled in Parts A/B with a residence in the 50 US states or the District of Columbia by September 1, 2014. New Medicare Parts A/B beneficiaries within 6 months after their 65th birthday were continuously included in the cohort after September 1, 2014, and followed through December 31, 2017. Participants were censored if they died, changed enrollment status, or developed a study outcome. Most of the analyses were conducted from 2018 to 2019, and additional analyses were performed from 2021 to 2022.Use of PCV13 vaccination 14 days or more before pneumonia hospitalization.Discrete-time survival models were used to estimate the incidence rate ratio (IRR) and number of pneumonia hospitalizations averted through PCV13 use. The adjusted IRR for the association of PCV13 vaccination with pneumonia hospitalization was used to estimate vaccine effectiveness (VE).At the end of follow-up (December 2017), 24 121 625 beneficiaries (13 593 975 women [56.4%]; 418 005 [1.7%] Asian, 1 750 807 [4.8%] Black, 338 044 [1.4%] Hispanic, 111 508 [0.5%] Native American, and 20 700 948 [85.8%] White individuals) were in the cohort; 4 936 185 (20.5%) had received PCV13 only, and 10 646 220 (79.5%) had not received any pneumococcal vaccines. More than half of the beneficiaries in the cohort were younger than 75 years, White, and had either immunocompromising or chronic medical conditions. Coverage with PCV13 increased from 0.8% (September 2014) to 41.5% (December 2017). The VE for PCV13 was estimated at 6.7% (95% CI, 5.9%-7.5%) for pneumonia, 4.7% (95% CI, 3.9%-5.6%) for non-HA pneumonia, and 5.8% (95% CI, 2.6%-8.9%) for LP. From September 2014 through December 2017, an estimated 35 127 pneumonia (95% CI, 33 011-37 270), 24 643 non-HA pneumonia (95% CI, 22 761-26 552), and 1294 LP (95% CI, 797-1819) hospitalizations were averted through PCV13 use.The study results suggest that PCV13 use was associated with reduced pneumonia hospitalization among Medicare beneficiaries 65 years or older, many of whom had underlying medical conditions. Increased PCV13 coverage and use of recently approved higher-valent pneumococcal conjugate vaccines may avert additional pneumonia hospitalizations in adults.
Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss
Authors: Terry Cheuk-Fung Yip, Vincent Wai-Sun Wong, Mandy Sze-Man Lai, Jimmy Che-To Lai, Vicki Wing-Ki Hui, Lilian Yan Liang, Yee-Kit Tse, Henry Lik-Yuen Chan, Grace Lai-Hung Wong
Journal: Journal of Hepatology (2022)
Precision Oncology: 2022 in Review
Authors: Ezra Rosen, Alexander Drilon, Debyani Chakravarty
Journal: Cancer Discovery (2022)

Summary: This article presents a review of the major advances and future implications in precision oncology accomplished in 2022 and centers on three primary pillars: advances in (i) rational drug design, (ii) study design, and (iii) novel biomarkers.
Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease
Authors: Atsushi Tanaka, Shinji Maeda, Takashi Nomura, Mara Anais Llamas-Covarrubias, Satoshi Tanaka, Lin Jin, Ee Lyn Lim, Hiromasa Morikawa, Yohko Kitagawa, Shuji Akizuki, Yoshinaga Ito, Chihiro Fujimori, Keiji Hirota, Tosei Murase, Motomu Hashimoto, Junichi Higo, Rose Zamoyska, Ryuzo Ueda, Daron M. Standley, Noriko Sakaguchi, Shimon Sakaguchi
Journal: The Journal of Experimental Medicine (2022)

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.
Cell Behavior Changes and Enzymatic Biodegradation of Hybrid Electrospun Poly(3‐hydroxybutyrate)‐Based Scaffolds with an Enhanced Piezoresponse after the Addition of Reduced Graphene Oxide
Authors: Roman V. Chernozem, Igor Pariy, Maria A. Surmeneva, Vladimir V. Shvartsman, Guillaume Planckaert, Joost Verduijn, Stef Ghysels, Anatolii Abalymov, Bogdan V. Parakhonskiy, Eric Gracey, Amanda Gonçalves, Sanjay Mathur, Frederik Ronsse, Diederik Depla, Doru C. Lupascu, Dirk Elewaut, Roman A. Surmenev, Andre G. Skirtach
Journal: Advanced Healthcare Materials (2022)

This is the first comprehensive study of the impact of biodegradation on the structure, surface potential, mechanical and piezoelectric properties of poly(3-hydroxybutyrate) (PHB) scaffolds supplemented with reduced graphene oxide (rGO) as well as cell behavior under static and dynamic mechanical conditions. There is no effect of the rGO addition up to 1.0 wt% on the rate of enzymatic biodegradation of PHB scaffolds for 30 d. The biodegradation of scaffolds leads to the depolymerization of the amorphous phase, resulting in an increase in the degree of crystallinity. Because of more regular dipole order in the crystalline phase, surface potential of all fibers increases after the biodegradation, with a maximum (361 ± 5 mV) after the addition of 1 wt% rGO into PHB as compared to pristine PHB fibers. By contrast, PHB-0.7rGO fibers manifest the strongest effective vertical (0.59 ± 0.03 pm V-1 ) and lateral (1.06 ± 0.02 pm V-1 ) piezoresponse owing to a greater presence of electroactive β-phase. In vitro assays involving primary human fibroblasts reveal equal biocompatibility and faster cell proliferation on PHB-0.7rGO scaffolds compared to pure PHB and nonpiezoelectric polycaprolactone scaffolds. Thus, the developed biodegradable PHB-rGO scaffolds with enhanced piezoresponse are promising for tissue-engineering applications.
Association of Hearing Aids and Cochlear Implants With Cognitive Decline and Dementia
Authors: Brian Sheng Yep Yeo, Harris Jun Jie Muhammad Danial Song, Emma Min Shuen Toh, Li Shia Ng, Cyrus Su Hui Ho, Roger Ho, Reshma Aziz Merchant, Benjamin Kye Jyn Tan, Woei Shyang Loh
Journal: JAMA Neurology (2022)

Hearing loss is associated with cognitive decline. However, it is unclear if hearing restorative devices may have a beneficial effect on cognition.To evaluate the associations of hearing aids and cochlear implants with cognitive decline and dementia.PubMed, Embase, and Cochrane databases for studies published from inception to July 23, 2021.Randomized clinical trials or observational studies published as full-length articles in peer-reviewed journals relating to the effect of hearing interventions on cognitive function, cognitive decline, cognitive impairment, and dementia in patients with hearing loss.The review was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) reporting guidelines. Two authors independently searched the PubMed, Embase, and Cochrane databases for studies relating to the effect of hearing interventions on cognitive decline and dementia in patients with hearing loss.Maximally adjusted hazard ratios (HRs) were used for dichotomous outcomes and ratio of means for continuous outcomes. Sources of heterogeneity were investigated using sensitivity and subgroup analyses, and publication bias was assessed using visual inspection, the Egger test, and trim and fill.A total of 3243 studies were screened; 31 studies (25 observational studies, 6 trials) with 137 484 participants were included, of which 19 (15 observational studies, 4 trials) were included in quantitative analyses. Meta-analysis of 8 studies, which had 126 903 participants, had a follow-up duration ranging from 2 to 25 years, and studied long-term associations between hearing aid use and cognitive decline, showed significantly lower hazards of any cognitive decline among hearing aid users compared with participants with uncorrected hearing loss (HR, 0.81; 95% CI, 0.76-0.87; I2 = 0%). Additionally, meta-analysis of 11 studies with 568 participants studying the association between hearing restoration and short-term cognitive test score changes revealed a 3% improvement in short-term cognitive test scores after the use of hearing aids (ratio of means, 1.03; 95% CI, 1.02-1.04, I2 = 0%).In this meta-analysis, the usage of hearing restorative devices by participants with hearing loss was associated with a 19% decrease in hazards of long-term cognitive decline. Furthermore, usage of these devices was significantly associated with a 3% improvement in cognitive test scores that assessed general cognition in the short term. A cognitive benefit of hearing restorative devices should be further investigated in randomized trials.